Cocaine dependence remains a substantial public health problem in the United States today. There is a wide and well-documented range of adverse health, psychological and social problems associated with chronic use of cocaine. However, in spite of two decades of intense research, effective pharmacotherapies for the treatment of addiction have not been identified. One of the key challenges in the successful treatment of cocaine addiction is decreasing the vulnerability of relapse to drug-taking which persists even after long periods of abstinence. Animal models have provided evidence that drug-seeking behavior arises from persistent neuroadaptations in mesolimbic dopaminergic circuitry during acquisition and cortico-striatal glutamatergic circuitry during relapse. Accordingly, the ventral striatum has been identified as a critical element of the neurocircuitry underlying drug and cue-induced reinstatement of cocaine-seeking after extinction training. However, recent evidence indicates that the habitual or compulsive quality of persistent drug-seeking in abstinent animals which do not undergo extinction training depends on the dorsal striatum (dSTR). Activity of metabotropic glutamate receptors (mGluRs) located in the ventral striatum is thought to be important for regulating cocaine-seeking behavior and cortico-striatal plasticity. Whether mGluRs in the dSTR are involved in relapse to cocaine-seeking after abstinence is not known. Our previous studies have shown that expression of the protein termed regulator of G-protein signaling 4 (RGS4) in the dSTR is regulated by acute or chronic noncontingent exposure to psychostimulants. RGS4 is a known potent negative regulator of G?i- and G?q- coupled receptors, including mGluR1/5 receptors. Cocaine self-administration followed by prolonged abstinence resulted in a decrease of RGS4 gene expression. Re-exposure to a cocaine-paired context, which resulted in robust cocaine-seeking, normalized the reduced expression of RGS4 gene expression in the dSTR. In addition, we have demonstrated that RGS4 protein in the dSTR directly associates with mGluR5-signalling assembly. Therefore, we hypothesize that changes in RGS4 levels result in altered mGluR5-mediated cellular signaling in the dSTR that contributes to increased vulnerability to relapse after abstinence. This hypothesis will be tested by addressing the following SPECIFIC AIMS: 1) To characterize changes in membrane- and mGluR5-associated RGS4 protein in the dSTR occurring with abstinence from cocaine self- administration and after relapse to cocaine-seeking. 2) To investigate the effects of RGS4 overexpression in the dSTR on relapse to cocaine-seeking after abstinence 3) To determine the effects of RGS4 overexpression on mGluR5-mediated cellular signaling in the dSTR during relapse to cocaine-seeking after abstinence. Completion of these aims will help to fill fundamental gaps in our understanding of the intracellular mechanisms underlying relapse to cocaine-seeking behavior and potentially lead to new pharmacotherapies for the treatment of addiction. PUBLIC HEALTH RELEVANCE: Cocaine addiction remains a substantial public health problem in the United States today. It is widely recognized that high risk of relapse even after long periods of abstinence represents one of the key challenges in successful treatment of cocaine addiction. This project proposal, entitled "Striatal RGS4 Interacts with mGluR5 Signaling in Relapse to Cocaine-seeking" is aimed to study neurobiological correlates of enduring vulnerability to relapse utilizing animal model with high face validity for human cocaine addiction.